Chiral separation of enantiomeric 1,2-diamines using molecular imprinting method and selectivity enhancement by addition of achiral primary amines into eluents.

The imprinted polymers based on a transient complex formation between methacrylic acid and template molecules were prepared by using methacrylic acid and ethylene dimethacrylate as a cross-linking agent. The template molecules used were (R,R)-cyclohexanediamine (1), (S,S)-1,2-diphenylethylenediamine (2) and (S)-1,1'-binaphthyl-2,2'-diamine (3). Another group of templates were those in which the amino group of these templates had been substituted by the hydroxy group: (R,R)-1,2-cyclohexanediol (4) and (S,S)-hydrobenzoin (5). Racemic 2 was separated by the polymer prepared with template 2 (P2) and that with template 1 (P1). Template 2 is larger than template 1 in steric bulkiness, but P1 was effective for the enantiomer separation of racemic 2. P1 was not effective for the separation of racemic 4. Enantioselectivity observed in racemic 2 in P2 was higher than that in racemic 1 in P1. P2 has no definite predetermined shape for solute 1, but it was capable of separating racemic 1. This separation should be thus ascribed to the orientation of at least two carbonyl groups reflecting the conformation of template 2 in P2 cavity. Racemic 5, having the same configuration of the two bulky phenyl groups as that of solute 2, was separated in P2. When the primary amines such as propylamine, cyclohexylamine and 1-adamantanamine were added into the acetic acid-methanol mixtures as eluents, both enantioselectivity and retentivity for racemic 2 were enhanced along with the remarkable peak tailing.     

A Dynamic Study of the Stereoisomerization of Pentaphenylethane by Molecular Mechanics Methods

Two conformations, 1 and 2 , of pentaphenylethane are compared. The ground state conformation 2 results from an earlier computational work by force fields procedures [1], whereas 1 has been more recently observed in the crystalline state by X-ray diffraction methods. The strain energy of 1 minimizes very close to the value computed for 2 . These conformations belong to two distinct minima of the potential energy surface and are at the most separated by a barrier of about 7 kcal/mol. The pathway converting 1 into its enantiomer is shown to run over a barrier of only 1.5 kcal/mol.     

Triggering G-Quadruplex Conformation Switching with [7]Helicenes

The dynamic interplay between two types of chiral structures; fully conjugated racemic hetero[7]helicenes and DNA strands prone to fold into G-quadruplex structures is described. Both the [7]helicenes and the G-quadruplex DNA structures exist in more than one conformation in solution. We show that the structures interact with and stabilise each other, mutually amplifying and stabilising certain conformations at increased temperatures. The [7]helicene ligands L1 and L2 stabilise the parallel conformation of k-ras significantly, whereas hybrid (K⁺) and antiparallel (Na⁺) h-telo G-quadruplexes are stabilised upon conformational switching into altered G-quadruplex conformations. Both L1 and L2 induce parallel G-quadruplexes from hybrid structures (K⁺) and L1 induces hybrid G-quadruplexes from antiparallel conformations (Na⁺). Enantioselective binding of one helicene enantiomer is observed for helicene ligand L2 , and VTCD melting experiments are used to estimate the racemisation barrier of the helicene.     

Two-dimensional supramolecular arrangements of enantiomers and racemic modification of 1,1'-binaphthyl-2,2'-dicarboxylic acid

Formation of adlayers of the optically active compound 1,1'-binaphthyl-2, 2'-dicarboxylic acid (BINAC) on iodine-modified Au (111) surfaces in perchloric acid was investigated by in situ scanning tunneling microscopy (STM). Highly ordered arrays formed on the surfaces via simple spontaneous adsorption from a solution of enantiomers or the racemic BINAC, in spite of the fact that BINAC has a three-dimensionally complex stereochemical structure. Adlayers of both enantiomers essentially shared the same enantiomorphous structure. Observed parameters of the rectangular unit cell lattice for arrays of both enantiomers of BINAC were a = 2.3 +/- 0.2 nm and b = 0.7 +/- 0.2 nm. On the other hand, racemic modification formed an entirely different adlayer, which consisted of an alternate alignment of the two enantiomers, with an oblique unit cell lattice with parameters of a = 1.2 +/- 0.2 nm, b = 0.8 +/- 0.1 nm, and 74 +/- 3 degrees . No domain composed of a single enantiomer was observed. The stronger hetero-intermolecular interactions of enantiomer couples led to the formation of an alternate arrangement in the array prepared by racemic modification.     

Anti and gauche conformers of an inorganic butane analogue, NH3BH2NH2BH3

The crystal structures of an inorganic butane analogue, NH(3)BH(2)NH(2)BH(3) (DDAB), were determined using single crystal X-ray diffraction, revealing both anti and gauche conformations. The anti conformation is stabilized by intermolecular dihydrogen bonds in the crystal whereas two gauche conformations of DDAB observed in its 18-crown-6 adducts are stabilized by an intramolecular dihydrogen bond. The two gauche conformations show rotational isomerization but whether they are a pair of enantiomers is yet to be defined.     

Molecular Mechanics Investigation of an Adenine-Adenine Non-Canonical Pair Conformational Change

Conformational changes are important in RNA for binding and catalysis and understanding these changes is important for understanding how RNA functions. Computational techniques using all-atom molecular models can be used to characterize conformational changes in RNA. These techniques are applied to an RNA conformational change involving a single base pair within a nine base pair RNA duplex. The Adenine-Adenine (AA) non-canonical pair in the sequence 5'GGUGAAGGCU3' paired with 3'PCCGAAGCCG5', where P is Purine, undergoes conformational exchange between two conformations on the timescale of tens of microseconds, as demonstrated in a previous NMR solution structure [Chen, G., et al., Biochemistry, 2006. 45: 6889-903]. The more populated, major, conformation was estimated to be 0.5 to 1.3 kcal/mol more stable at 30 °C than the less populated, minor, conformation. Both conformations are trans-Hoogsteen/sugar edge pairs, where the interacting edges on the adenines change with the conformational change. Targeted Molecular Dynamics (TMD) and Nudged Elastic Band (NEB) were used to model the pathway between the major and minor conformations using the AMBER software package. The adenines were predicted to change conformation via intermediates in which they are stacked as opposed to hydrogen-bonded. The predicted pathways can be described by an improper dihedral angle reaction coordinate. Umbrella sampling along the reaction coordinate was performed to model the free energy profile for the conformational change using a total of 1800 ns of sampling. Although the barrier height between the major and minor conformations was reasonable, the free energy difference between the major and minor conformations was the opposite of that expected based on the NMR experiments. Variations in the force field applied did not improve the misrepresentation of the free energies of the major and minor conformations. As an alternative, the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approximation was applied to predict free energy differences between the two conformations using a total of 800 ns of sampling. MM-PBSA also incorrectly predicted the major conformation to be higher in free energy than the minor conformation.     

The "nearest single neighbor" method-finding families of conformations within a sample

A simple method for self-organization of conformation samples into families is presented. According to this method, any large sample of molecular conformations may be reorganized according to the nearest single root-mean-square displacement (rmsd) neighbor, starting at any chosen "seed" conformation. Following such reordering, conformational families may be determined by a novel process that maximizes family sizes while minimizing family mixing. This process eliminates much of the arbitrariness that was inherent in most of the related methods of conformation clustering. We demonstrate the construction of rmsd matrices and discuss the convergence criteria for the sample size as well as criteria for determining the cutoff value for the definition of families in each sample. The method is invariant to changes of the "seed" conformation. After applying this method, families of conformations may be more easily recognized in graphic matrices. The method has been applied to the analysis of the conformational space of two cyclic peptides. It is also shown that the "organized" conformational space, at least in those specific examples, has an energy topology that reminds of energy basins. The method is general and applicable to molecules of any type.     

Synthesis and evaluation of atropos dihydro-5H-dibenzazepinium halide PTCs derived from α-methylbenzylamine

A short synthetic route to diastereoisomeric atropos dihydro-5H-dibenz[c,e]azepinium salts via reaction of a single enantiomer of (R)-α-methylbenzylamine with a racemic atropos biphenol derivative is described. Compounds prepared via this approach are used to provide strong evidence that structurally related tropos dihydro-5H-dibenz[c,e]azepinium salts preferentially react via a single conformation in PTC reactions involving glycine imine enolates.     

Corynebactin and a serine trilactone based analogue: chirality and molecular modeling of ferric complexes

Because the hydrolysis of ferric ion makes it very insoluble in aerobic, near neutral pH environments, most species of bacteria produce siderophores to acquire iron, an essential nutrient. The chirality of the ferric siderophore complex plays an important role in cell recognition, uptake, and utilization. Corynebactin, isolated from Gram-positive bacteria, is structurally similar to enterobactin, a well-known siderophore first isolated from Gram-negative bacteria, but contains L-threonine instead of L-serine in the trilactone backbone. Corynebactin also contains a glycine spacer unit in each of the chelating arms. A hybrid analogue (serine-corynebactin) has been prepared which has the trilactone ring of enterobactin and the glycine spacer of corynebactin. The chirality and relative conformational stability of the three ferric complexes of enterobactin, corynebactin, and the hybrid have been investigated by molecular modeling (including MM3 and pBP86/DN density functional theory calculations) and circular dichroism spectra. While enterobactin forms a Delta-ferric complex, corynebactin is Lambda. The hybrid serine-corynebactin forms a nearly racemic mixture, with the Lambda-conformer in slight excess. Each ferric complex has four possible isomers depending on the metal chirality and the conformation of the trilactone ring. For corynebactin, the energy difference between the two possible Lambda conformations is 2.3 kcal/mol. In contrast, only 1.5 kcal/mol separates the inverted Lambda- and normal Delta-configuration for serine-corynebactin. The small energy difference of the two lowest energy configurations is the likely cause for the racemic mixture found in the CD spectra. Both the addition of a glycine spacer and methylation of the trilactone ring (serine to threonine) favor the Lambda-conformation. These structural changes suffice to change the chirality from all Delta (enterobactin) to all Lambda (corynebactin). The single change (glycine spacer) of the hybrid ferric serine-corynebactin gives a mixture of Delta and Lambda, with the Lambda in slight excess.     

DFT conformational studies of alpha-maltotriose

Recent DFT optimization studies on alpha-maltose improved our understanding of the preferred conformations of alpha-maltose. The present study extends these studies to alpha-maltotriose with three alpha-D-glucopyranose residues linked by two alpha-[1-->4] bridges, denoted herein as DP-3's. Combinations of gg, gt, and tg hydroxymethyl groups are included for both "c" and "r" hydroxyl rotamers. When the hydroxymethyl groups are for example, gg-gg-gg, and the hydroxyl groups are rotated from all clockwise, "c", to all counterclockwise, "r", the minimum energy positions of the bridging dihedral angles (phi(H) and psi(H)) move from the region of conformational space of (-, -), relative to (0 degrees , 0 degrees), to a new position defined by (+, +). Further, it was found previously that the relative energies of alpha-maltose gg-gg-c and "r" conformations were very close to one another; however, the DP-3's relative energies between hydroxyl "c" or "r" rotamers differ by more than one kcal/mol, in favor of the "c" form, even though the lowest energy DP-3 conformations have glycosidic dihedral angles similar to those found in the alpha-maltose study. Preliminary solvation studies using COSMO, a dielectric solvation method, point to important solvent contributions that reverse the energy profiles, showing an energy preference for the "r" forms. Only structures in which the rings are in the chair conformation are presented here.     

On the nature of the lowest triplet excited state of the [Rh 2(1,3-diisocyanopropane)(4)]2+ ion

The nature of the ground state and the lowest triplet excited state of the [Rh(2)(1,3-diisocyanopropane)(4)](2+) ion have been investigated by the density functional theory. Two locally stable geometrical conformations are found on the potential energy surfaces of both the ground and excited states, corresponding to the eclipsed and twisted conformations, the eclipsed conformation being more stable and having the shorter Rh-Rh bond length. While the Rh-Rh distances of the two conformations differ by approximately 0.4 A, they shorten to the same value upon excitation ( approximately 3.1 A). The excited state originates from the d(z)()()2 (metal antibonding) to p(z)() (ligand-metal bonding) electronic transition. The Mayer Rh-Rh bond order increases from approximately 0.2 to more than 0.8 upon excitation, while the Rh-C(N) bond order shows a slight decrease. A topological bond path between the Rh atoms is found in both the ground and excited states, while the electron localization function (ELF) indicates weak Rh-Rh covalent bonding for the excited state only.     

On-line racemization by high-performance liquid chromatography

An on-column stopped-flow bidimensional recycling HPLC procedure was developed to obtain an enantiomeric enrichment starting from a racemic mixture. The method developed was applied to two chiral compounds of pharmaceutical interest, (±)(R,S)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide (1) and (±)-7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide ((±)IDRA21, (2)), since the pharmacological activity of the two benzothiadiazine derivatives investigated has been ascribed to only one enantiomer. Starting from a racemic mixture it was possible to obtain about 95% of pure enantiomer. The procedure was applied both in reverse-phase mode and in normal-phase mode. The scaled up and automatization of the novel analytical HPLC procedure represents a powerful tool to obtain pure enantiomer starting from racemic compounds without cumbersome stereoselective synthesis or expensive enantiopurification processes.     

Gas-phase conformations of deprotonated trinucleotides (dGTT-, dTGT-, and dTTG-): the question of zwitterion formation

The gas-phase conformations of a series of trinucleotides containing thymine (T) and guanine (G) bases were investigated for the possibility of zwitterion formation. Deprotonated dGTT-, dTGT-, and dTTG- ions were formed by MALDI and their collision cross-sections in helium measured by ion mobility based methods. dTGT- was theoretically modeled assuming a zwitterionic and non-zwitterionic structure while dGTT- and dTTG- were considered "control groups" and modeled only as non-zwitterions. In the zwitterion, G is protonated at the N7 site and the two neighboring phosphates are deprotonated. In the non-zwitterion, G is not protonated and only one phosphate group is deprotonated. Two conformers, whose cross-sections differ by 17 +/- 2 A2, are observed for dTGT- in the 80 K experiments. Multiple conformers are also observed for dGTT- and dTTG- at 80 K, though relative cross-section differences between the conformers could not be accurately obtained. At higher temperatures (>200 K), the conformers rapidly interconvert on the experimental time scale and a single "time-averaged" conformer is observed in the ion mobility data. Theory predicts only one low-energy conformation for the zwitterionic form of dTGT- with a cross-section 8% smaller than experimental values. Additionally, the extra H+ on G does not bridge both phosphates. Thus, dTGT- does not appear to be a stable zwitterion in the gas-phase. Theory does, however, predict two low-energy conformers for the non-zwitterionic form of dTGT- that differ in cross-section by 18 +/- 3 A2, in good agreement with the experiment. In the smaller cross-section form (folded conformer), G and one of the T bases are stacked while the other T folds towards the stacked pair and hydrogen bonds to G. In the larger cross-section form (open conformer), the unstacked T extends away from the T/G stacked pair. Similar folded and open conformers are predicted for all three trinucleotides, regardless of which phosphate is deprotonated.     

Coordination to metal centers: a tool to fix high energy conformations in organic molecules. Application to 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene and related macrocycles

The solid state conformational preferences of ligand 2,4,4-trimethyl-1,5,9-triazacyclododec-1-ene (L1) and its 9-methyl derivative (L2) in transition metal complexes have been determined by a probabilistic method using data retrieved from the Cambridge Structural Database. These macrocyclic compounds, as ligands, tend to adopt a preferential conformation (85% of cases). The ring containing the C=N bond adopts a distorted half-chair conformation, the ring defined by both the N-sp(3) shows a distorted envelope conformation, and the remaining ring exhibits a chair conformation. This conformation corresponds to the enantiomer pair R(N5)S(N9)S(P)/S(N5)R(N9)R(P). Molecular mechanics calculations demonstrate that this is a high energy conformation for the organic molecule, far from the energy minimum. Two other enantiomer pairs are observed in experimental structures. The influence of the coordination on the conformation of the organic ligands has been studied by DFT calculations, and a clear correlation with the geometry of the coordination sphere has been found.     

Assignment of absolute configuration of a chiral phenyl-substituted dihydrofuroangelicin

A phenyl-substituted chiral dihydrofuroangelicin, 4-methyl-8-(2-E-phenylethenyl)-8,9-dihydro-2H-furo[2,3-h]- 1-benzopyran-2-one, synthesized in racemic form, has been resolved by HPLC chiral separation, and its absolute configuration determined by the non-empirical exciton chirality method. The solution conformation has been investigated through NMR and molecular modeling methods: two minima found by molecular mechanics and DFT methods are in keeping with observed 1H-1H 3J coupling constants and NOE effects. The experimental CD spectrum for the second eluted enantiomer shows a positive couplet between 230 and 350 nm (amplitude A = + 15.7); by application of the exciton chirality method, the absolute configuration of this enantiomer at C8 is determined as (S). The experimental spectrum is in very good agreement with the one evaluated by means of DeVoe coupled-oscillator calculations, using the DFT calculated geometries.     

Toward accurate relative energy predictions of the bioactive conformation of drugs

Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol(-1) of a local minimum, with penalties above 2.0 kcal mol(-1) being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery.     

Electronic states of tetrahydrofuran molecules studied by electron collisions

Electronic states of tetrahydrofuran molecules were studied in the excitation energy range 5.5-10 eV using the technique of electron energy loss spectroscopy in the gas phase. Excitation from the two conformations, C(2) and C(s), of the ground state of the molecule are observed in the measured energy loss spectra. The vertical excitation energies of the (3)(n(o)3s) triplet state from the C(2) and C(s) conformations of the ground state of the molecule are determined to be 6.03 ± 0.02 and 6.25 ± 0.02 eV, respectively. The singlet-triplet energy splitting for the n(o)3s configuration is determined to be 0.31 eV. It is also found that excitation from the C(s) conformation of the ground state has a higher cross section than that from the C(2) conformation.     

New insights in the electrocatalytic proton reduction and hydrogen oxidation by bioinspired catalysts: a DFT investigation

In this paper, we present a DFT study of the proton reduction mechanism catalyzed by the complex [Ni(P?(H)N?(H))?](2+), bioinspired from the hydrogenases. A detailed analysis of the reactive isomers is discussed together with the localizations of the transitions states and energy minima. The reactive catalytic species is a biprotonated Ni(0) complex that can show different conformations and that can be protonated on different sites. The energies of the different conformations and biprotonated species have been calculated and discussed. Energy barriers for two different reaction mechanisms have been identified in solvent and in gas phase. Frequency calculations have been performed to check the nature of the energy minima and for the calculations of entropic energetic terms and zero point energies. We show that only one conformation is mostly reactive. All the others species are nonreactive in their original form, and they have to pass through conformational barriers in order to transform in the reactive species.     

High-performance liquid chromatography of ternary nickel dithiocarbamate complexes derived from some sympathomimetic drugs

Summary Nickel dithiocarbamate complexes derived from some sympathomimetic drugs are examined on silica Radial-Pak columns using binary solvents containing a small percentage of an organic polar modifier. Both the type and concentration of this modifier was found to influence the separation of the ternary from the parent binary complexes. When the two ligands in a ternary complex are racemic to each other, separation of the ternary complex is only possible when certain structural requirements of the molecule are fulfilled. Ternary complexes which contain structurally similar, but nonracemic ligands, are shown to be readily separated from binary complexes. When two such complexes differ only in that one of the ligands in one is enantiomeric to a ligand in the second complex, then it can be shown that the ternary complex with the (+) enantiomer ligand elutes faster from the silica column than the one with the (–) enantiomer ligand. An example of the use of ternary complexes for the identification of optical and structurally related impurities in pharmaceutical products is also given.     

Quantifying polypeptide conformational space: sensitivity to conformation and ensemble definition

Quantifying the density of conformations over phase space (the conformational distribution) is needed to model important macromolecular processes such as protein folding. In this work, we quantify the conformational distribution for a simple polypeptide (N-mer polyalanine) using the cumulative distribution function (CDF), which gives the probability that two randomly selected conformations are separated by less than a "conformational" distance and whose inverse gives conformation counts as a function of conformational radius. An important finding is that the conformation counts obtained by the CDF inverse depend critically on the assignment of a conformation's distance span and the ensemble (e.g., unfolded state model): varying ensemble and conformation definition (1 --> 2 A) varies the CDF-based conformation counts for Ala(50) from 10(11) to 10(69). In particular, relatively short molecular dynamics (MD) relaxation of Ala(50)'s random-walk ensemble reduces the number of conformers from 10(55) to 10(14) (using a 1 A root-mean-square-deviation radius conformation definition) pointing to potential disconnections in comparing the results from simplified models of unfolded proteins with those from all-atom MD simulations. Explicit waters are found to roughen the landscape considerably. Under some common conformation definitions, the results herein provide (i) an upper limit to the number of accessible conformations that compose unfolded states of proteins, (ii) the optimal clustering radius/conformation radius for counting conformations for a given energy and solvent model, (iii) a means of comparing various studies, and (iv) an assessment of the applicability of random search in protein folding.